REVI EW ARTI CLE DOI 10. 1111/j . 1365- 2133. 2005. 06905.

x
The new World Health OrganizationEuropean Organization
for Research and Treatment of Cancer classication for
cutaneous lymphomas: a practical marriage of two giants
D.N. Slater
Department of Histopathology, Royal Hallamshire Hospital, Shefeld S10 2JF, U.K.
Correspondence
David Slater.
E-mail: david.slater@sth.nhs.uk
Accepted for publication
3 June 2005
Key words:
classication, cutaneous lymphoma, European
Organization for Research and Treatment of
Cancer, World Health Organization
Conicts of interest:
None declared.
Summary
Following consensus meetings of the two parent organizations, a new World
Health OrganizationEuropean Organization for Research and Treatment of Can-
cer (WHOEORTC) classication for primary cutaneous lymphomas has recently
been published. This important development will now end the ongoing debate
as to which of these was the preferred classication. The new classication will
facilitate more uniformity in diagnosis, management and treatment of cutaneous
lymphomas. In particular, it provides a useful distinction between indolent and
more aggressive types of primary cutaneous lymphoma and provides practical
advice on preferred management and treatment regimens. This will thereby pre-
vent patients receiving high-grade treatment for low-grade biological disease.
This review focuses on those diseases which have found new consensus agree-
ment compared with the original WHO and EORTC classications. In cutaneous
T-cell lymphomas, these include folliculotropic mycosis fungoides, dening fea-
tures of Sezary syndrome, primary cutaneous CD30+ lymphoproliferative disor-
ders (primary cutaneous anaplastic large cell lymphoma, lymphomatoid papulosis
and borderline lesions) and subcutaneous panniculitis-like T-cell lymphoma. Pri-
mary cutaneous CD4+ small medium-sized pleomorphic T-cell lymphoma, pri-
mary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma and
cutaneous c d T-cell lymphoma are allocated provisional entry status and thereby
afford better denitions for some cases of currently unspecied primary cutane-
ous peripheral T-cell lymphoma. In cutaneous B-cell lymphomas, diseases which
have found new consensus agreement include primary cutaneous marginal zone
B-cell lymphoma, primary cutaneous follicular centre lymphoma, primary cuta-
neous diffuse large B-cell lymphoma, leg type and primary cutaneous diffuse
large B-cell lymphoma, other. CD4+ CD56+ haematodermic neoplasm (early
plasmacytoid dendritic cell leukaemia lymphoma) now appears as a precursor
haematological neoplasm and replaces the previous terminology of blastic NK-cell
lymphoma. Other haematopoietic and lymphoid tumours involving the skin, as
part of systemic disease, will appear in the forthcoming WHO publication Tumours
of the Skin. The new classication raises interesting new problems and questions
about primary cutaneous lymphoma and some of these are discussed in this art-
icle. It is, however, a splendid signpost indicating the direction in which research
in cutaneous lymphoma needs to go. In the interim, we have an international
consensus classication which is clinically meaningful.
The classication of cutaneous lymphoma continues to evolve
rapidly. Although designed primarily for general lymphoid
neoplasms, the Revised EuropeanAmerican Lymphoma
(REAL) classication was the rst to be based on denable
clinicopathological entities.
1
Proposals were made to apply the
REAL classication to the skin, but these received little promin-
ence owing to the emergence of the European Organization for
Research and Treatment of Cancer (EORTC) classication.
2
The
874 2005 British Association of Dermatologists British Journal of Dermatology 2005 153, pp874880
EORTC classication for primary cutaneous lymphoma used a
similar approach to the REAL, basing diagnoses on a combina-
tion of clinical, histological, immunohistochemical and geno-
typic criteria. In addition, the EORTC classication enjoyed
substantial support because of its identication of distinct cuta-
neous disease entities, with well-dened clinical and histologi-
cal features, including a predictable clinical course, response to
therapy and prognosis. The World Health Organization
(WHO) classication of tumours of haematopoietic and lym-
phoid tissues was the rst worldwide consensus classication
of these neoplasms.
3
The WHO adopted the principles of the
REAL and recognized disease entities based on a combination
of morphology, immunophenotypic, genetic and clinical fea-
tures. The WHO classication undoubtedly received support
with reference to skin lymphoma, as the number of named pri-
mary cutaneous entities increased signicantly from those in
the REAL classication. Although both the EORTC and WHO
classications were signicant improvements on the original
REAL classication, both classications were recognized to have
signicant shortcomings and this resulted in considerable con-
tinuing debate.
4
In particular, this related to the classication
of cutaneous T-cell lymphomas (CTCLs) other than mycosis
fungoides (MF) and Sezary syndrome (SS), and cutaneous
B-cell lymphomas (CBCLs). During consensus meetings in
2003 and 2004, however, representatives of both organizations
reached agreement on a new classication which has been des-
ignated the WHOEORTC classication (Table 1).
5
The basic premise of the new classication is that primary
cutaneous lymphomas often have a completely different clin-
ical behaviour and prognosis from histologically similar nodal
lymphomas and therefore require different types of manage-
ment and treatment.
This review will focus on those diseases that have achieved
consensus reclassication since their inclusion in the original
EORTC and or WHO publications. Sensibly, the term primary
cutaneous lymphoma is now dened as cases that present in
the skin with no evidence of extracutaneous disease at the
time of presentation. For purists, however, this could cause
problems in the inclusion of entities such as precursor haema-
tological neoplasm in this grouping.
Mycosis fungoides
Surprisingly, the publication provides little guidance on the
early diagnosis of MF. The main issue addressed is the minor
redesignation of folliculotropic and granulomatous slack skin
variants subtypes of MF. Other clinical, histological and pheno-
typic variants, such as the increasingly recognized papular
variant of MF, receive no consideration.
Folliculotropic mycosis fungoides
This was previously designated as MF-associated follicular
mucinosis in both EORTC and WHO classications. Recent
studies, however, have shown no differences in clinical pres-
entation and behaviour between cases of folliculotropic MF
with or without associated follicular mucinosis. Accordingly,
it has been agreed that the preferred term is that of folliculo-
tropic MF. From the clinical point of view, the most relevant
feature is the deeper localization of the neoplastic inltrates
and the reduced response to skin-targeted therapies such as
psoralen plus ultraviolet A treatment.
Granulomatous slack skin
Although originally regarded by the EORTC as a provisional
entry, the new classication formally recognizes it as a formal
variant of MF.
Sezary syndrome
The WHOEORTC appear supportive of the recent report from
the International Society for Cutaneous Lymphomas (ISCL) on
erythrodermic CTCL.
6
In this, the criteria recommended for
the diagnosis of SS include one or more of the following: an
absolute Sezary cell count of at least 1000 cells mm
)3
, a
CD4 CD8 ratio of 10 or higher caused by an increase in circu-
lating T cells and or an aberrant loss or expansion of
pan-T-cell markers evidenced by ow cytometry, increased
lymphocyte counts with evidence of a T-cell clone in the
Table 1 World Health OrganizationEuropean Organization for
Research and Treatment of Cancer classication of cutaneous
lymphomas with primary cutaneous manifestations
Cutaneous T-cell and NK-cell lymphomas
Mycosis fungoides
Mycosis fungoides variants and subtypes
Folliculotropic mycosis fungoides
Pagetoid reticulosis
Granulomatous slack skin
Sezary syndrome
Adult T-cell leukaemia lymphoma
Primary cutaneous CD30+ lymphoproliferative disorders
Primary cutaneous anaplastic large cell lymphoma
Lymphomatoid papulosis
Subcutaneous panniculitis-like T-cell lymphoma
Extranodal NK T-cell lymphoma, nasal type
Primary cutaneous peripheral T-cell lymphoma, unspecied
Primary cutaneous aggressive epidermotropic CD8+ T-cell
lymphoma (provisional)
Cutaneous c d T-cell lymphoma (provisional)
Primary cutaneous CD4+ small medium-sized pleomorphic
T-cell lymphoma (provisional)
Cutaneous B-cell lymphomas
Primary cutaneous marginal zone B-cell lymphoma
Primary cutaneous follicle centre lymphoma
Primary cutaneous diffuse large B-cell lymphoma, leg type
Primary cutaneous diffuse large B-cell lymphoma, other
Intravascular large B-cell lymphoma
Precursor hematological neoplasm
CD4+ CD56+ hematodermic neoplasm (blastic NK-cell
lymphoma)
2005 British Association of Dermatologists British Journal of Dermatology 2005 153, pp874880
The new WHOEORTC classication for cutaneous lymphomas, D.N. Slater 875
blood by Southern blot or polymerase chain reaction tech-
niques or a chromosomally abnormal T-cell clone. The WHO
EORTC acknowledge that SS is part of a broader spectrum of
erythrodermic CTCL, and that alternative staging systems for
assessment of the degree of peripheral blood involvement in
erythrodermic CTCL are necessary. However, until the results
of an ISCL study investigating the clinical validity of these pro-
posals are available, demonstration of a T-cell clone (prefer-
ably of the same T-cell clone in skin and peripheral blood) in
combination with one of the above-mentioned cytomorpho-
logical or immunophenotypical criteria are suggested as min-
imal criteria for the diagnosis of SS to exclude patients with
benign inammatory conditions simulating SS. With regard to
the treatment of SS, they provide an observatory comment
that, although extracorporeal photopheresis is currently
favoured over traditional low-dose chemotherapy, this has not
yet been substantiated by randomized controlled trials.
Primary cutaneous CD30+ lymphoproliferative
disorders
Primary cutaneous anaplastic large cell lymphoma (C-ALCL)
and lymphomatoid papulosis (LYP) are presented as entities
on the same disease spectrum and it is emphasized that histo-
logical criteria alone are often insufcient to differentiate
them. The term borderline refers to those cases in which,
despite careful clinicopathological correlation, a denitive dis-
tinction between C-ALCL and LYP cannot be made. In general,
this approach is very much that originally recommended by
the EORTC. In particular, LYP no longer lies under the previ-
ous WHO title of T-cell proliferation of uncertain malignant
potential. The new classication also demonstrates a redeni-
tion of the 2001 WHO borderline group in this area. LYP type
C is now more appropriately placed with other types of LYP
and C-ALCL of LYP type receives no specic designation.
Primary cutaneous anaplastic large cell lymphoma
Although adopting the 2001 WHO denition of primary
C-ALCL, the entity now incorporates the EORTC concept of
including not only anaplastic but also pleomorphic and immu-
noblastic cells. Clinical features mentioned, which overlap con-
siderably with LYP, include multifocal lesions in about 20% of
patients, the ability of lesions to show partial or complete spon-
taneous regression, the tendency towards cutaneous relapse,
extracutaneous dissemination in approximately 10% of cases
and potential spread to regional lymph nodes. The prognosis is
stated to be favourable, with a 10-year disease-related survival
exceeding 90% and patients with multifocal skin lesions or
regional lymph node involvement having a similar prognosis.
As in the original EORTC classication, the different mor-
phological cell types are recognized to have no differences in
terms of clinical presentation, behaviour or prognosis. Radio-
therapy, surgical excision or low-dose methotrexate are
recommended as the primary treatments and doxorubicin-
based multiagent chemotherapy is advised to be restricted to
extracutaneous or rapidly progressive skin disease. In addition,
the histological diagnostic difculty of ulcerated lesions is
highlighted. These may show a LYP-like histology with an
abundant inltrate of reactive T cells, histiocytes, eosinophils
and or neutrophils, plus prominent epidermal hyperplasia but
with relatively few CD30+ cells.
Lymphomatoid papulosis
The new classication adopts the well-established EORTC clas-
sication of dividing LYP into types A, B and C. The latter
represents patients with clinical features of LYP but histologi-
cally demonstrating a monotonous population or substantial
clusters of large CD30+ T cells with relatively few admixed
inammatory cells. Although LYP type B is understandably
included, the tendency towards an absence of CD30+ T cells
is paradoxical for a disease under a generic heading incorpor-
ating this CD number. The new publication emphasizes that,
as no curative therapy is available and none of the available
treatment modalities affects the natural course of the disease,
the short-term benets of active treatment (such as low-dose
oral methotrexate) should be balanced carefully against the
potential side-effects. Accordingly, whenever possible, long-
term follow-up without active treatment should always be
considered.
Subcutaneous panniculitis-like T-cell
lymphoma
This cytotoxic T-cell lymphoma was previously dened as a
specic entity by the WHO but was regarded as a provisional
entity by the EORTC. The entity has, however, been signi-
cantly redened in the new WHOEORTC classication. Cases
with an a b T-cell receptor (TCR) phenotype are usually
CD8+, are restricted to the subcutaneous tissue and often run
an indolent course. In contrast, cases with a c d TCR pheno-
type are typically CD4 and CD8, often express CD56, may
involve the epidermis and have a poor prognosis. On that
basis, the category of subcutaneous panniculitis-like T-cell
lymphoma (SPTCL) in the WHOEORTC classication is now
restricted to cases with an a b TCR phenotype, whereas cases
with a c d TCR phenotype are placed in the new category of
cutaneous c d T-cell lymphoma (CGD-TCL).
Although patients have classically often been treated with
doxorubicin-based chemotherapy and radiotherapy, recent
studies suggest that many patients can be controlled for long
periods of time with systemic corticosteroids.
Extranodal NK T-cell lymphoma, nasal type
The new WHOEORTC classication has adopted the 2001
WHO entry, which was totally missing in the EORTC classi-
cation. The skin is the most common site of involvement after
the nasal cavity nasopharynx, and skin involvement may be a
primary or secondary manifestation of the disease. The disease
is aggressive, with a median survival of 5 months for patients
2005 British Association of Dermatologists British Journal of Dermatology 2005 153, pp874880
876 The new WHOEORTC classication for cutaneous lymphomas, D.N. Slater
with cutaneous and extracutaneous disease. In patients pre-
senting with only skin lesions, however, a median survival of
27 months is reported. Although systemic chemotherapy is
the rst treatment of choice, the results are often disappoint-
ing. Most cases are positive for CD56 and EpsteinBarr virus
(EBV), although rare CD56 cases have been reported.
Hydroa vacciniforme-like CTCL is a rare type of EBV-associ-
ated lymphoma of CD8+ cytotoxic T cells, which affects chil-
dren almost exclusively in Latin America and Asia. This is
considered by the WHOEORTC to be a new variant of extra-
nodal NK T-cell lymphoma, nasal type, although this could be
debated given a signicant number of CD56 cases.
Primary cutaneous peripheral T-cell
lymphoma, unspecied
Peripheral T-cell lymphoma (PTL), unspecied in the
WHO classication, represents a heterogeneous group which
includes all T-cell neoplasms that do not t into any of the
better dened subtypes of T-cell lymphoma leukaemia. Recent
studies have, however, suggested that some cases may repre-
sent specic entities and accordingly have been given the sta-
tus of provisional entries in the WHOEORTC classication.
For remaining cases that do not t into these provisional enti-
ties, the designation PTL, unspecied is still maintained. In all
cases a diagnosis of MF must be ruled out by clinical history
and examination.
Primary cutaneous aggressive epidermotropic CD8+
cytotoxic T-cell lymphoma (provisional entry)
Clinically, this lymphoma is characterized by the presence of
localized or disseminated eruptive papules, nodules and
tumours showing central ulceration and necrosis or by super-
cial, hyperkeratotic patches and plaques.
7
The clinical features
are very similar to those observed in patients with CGD-TCL.
The lymphoma may disseminate to other visceral sites (lung,
testis, central nervous system and oral mucosa) but lymph
nodes are often spared. Histologically, there is pronounced
epidermotropism and the cells are of CD8+ CD56 cytotoxic
T-cell type. The lymphoma has an aggressive clinical course,
with a median survival of 32 months. There is no difference
in survival between cases of small or large cell morphology.
Patients are generally treated with doxorubicin-based multi-
agent chemotherapy. Patients with so-called disseminated pag-
etoid reticulosis (KetronGoodman disease) are now generally
regarded as representing this type of lymphoma, CGD-TCL or
tumour-stage MF.
Cutaneous c d T-cell lymphoma (provisional entry)
CGD-TCL is a lymphoma composed of activated c d T cells
with a cytotoxic phenotype. This group includes cases previ-
ously known as SPTCL with a c d TCR phenotype. A similar
and possibly related condition may be present primarily at
mucosal sites. Whether cutaneous and mucosal c d T-cell
lymphoma are all part of a single disease, i.e. mucocutaneous
c d T-cell lymphoma, is not yet clear. Distinction between
primary and secondary cutaneous cases is not useful as all
cases have a poor prognosis. CGD-TCL generally presents with
disseminated plaques and or ulceronecrotic nodules or
tumours, particularly on the extremities. Involvement of mu-
cosal and other extranodal sites is frequently observed but
involvement of lymph nodes, spleen or bone marrow is
uncommon. A haemophagocytic syndrome may occur in
patients with panniculitis-like tumours. The histological pat-
tern may be epidermotropic, dermal or subcutaneous. The
neoplastic cells are usually of medium to large blast cell type
and angioinvasion and necrosis are common.
The tumour cells characteristically have a CD56 phenotype
with strong expression of cytotoxic proteins, and most cases
lack CD4 and CD8. Patients should be treated with systemic
chemotherapy but the results are often disappointing, with a
median survival of 15 months. There is a trend for decreased
survival in patients with subcutaneous fat involvement in com-
parison with those with only epidermal and dermal involve-
ment. Unfortunately, their immunohistological diagnosis
using c TCR antibodies still requires the use of frozen tissue.
Primary cutaneous CD4+ small medium-sized
pleomorphic T-cell lymphoma (provisional entity)
Characteristically, these tumours present with a solitary plaque
or tumour, generally on the upper half of the body, but
without a history of patches and plaques to suggest MF. In
contrast to the EORTC classication, the term small medium-
sized pleomorphic CTCL is restricted to cases with a CD4
T-cell phenotype.
8
By denition, the number of large cells
present must be less than 30%. These lymphomas have a
rather favourable prognosis, with an estimated 5-year survival
of approximately 6080%. Surgical excision or radiotherapy is
the preferred mode of treatment, although cyclophosphamide
may be effective in patients with more generalized skin dis-
ease. Optimal treatment for this group, however, has still to
be dened.
Primary cutaneous peripheral T-cell lymphoma,
unspecied
After the three provisional entries have been excluded, the
remaining cases in this category usually display large neoplas-
tic cells, which represent at least 30% of the cell population.
CD30 staining is negative or restricted to a few scattered cells
and rare cases may show coexpression of CD56. The prognosis
is generally poor, with a 5-year survival rate of less than 20%.
Patients should be treated with multiagent chemotherapy.
CD4+ CD56+ hematodermic neoplasm (blastic
NK-cell lymphoma)
In the WHO classication, blastic NK-cell lymphoma
was included as a clinically aggressive neoplasm with a high
2005 British Association of Dermatologists British Journal of Dermatology 2005 153, pp874880
The new WHOEORTC classication for cutaneous lymphomas, D.N. Slater 877
incidence of cutaneous involvement and risk of leukaemic dis-
semination. More recent studies, however, have suggested a
derivation from a plasmacytoid dendritic cell precursor.
9
Accordingly, CD4+ CD56+ hematodermic neoplasm or early
plasmacytoid dendritic cell leukaemia lymphoma have been
suggested as more appropriate terms. Approximately 50% of
patients have nodal or bone marrow involvement at presenta-
tion and the blast cells are of CD4+, CD56+ and CD123+
phenotype.
Recent studies suggest that patients are better treated with
acute leukaemia regimens and although complete remission
can be initially induced, quick relapse unresponsive to further
chemotherapy is frequent. Median survival is approximately
14 months.
Primary cutaneous marginal zone B-cell
lymphoma
After many years of resistance, the EORTC has now accepted
this as the favoured diagnostic term and has also accepted that
it incorporates their previous entries of immunocytoma and
plasmacytoma. The recommended term in the WHOEORTC
classication is certainly more user-friendly than the lengthy
2001 WHO term of extranodal marginal zone B-cell lym-
phoma of mucosa-associated lymphoma tissue (MALT lym-
phoma). The neoplastic cells are bcl-2+ but, in contrast to
primary cutaneous follicular centre lymphoma (PCFCL), are
CD10 and bcl-6. The prognosis of primary cutaneous mar-
ginal zone lymphoma (PCMZL) is stated to be excellent, with
a 5-year survival close to 100%. Emphasis is given with regard
to the propensity of lesions to involve the trunk or arms pref-
erentially, and a tendency to be multifocal and to recur. In
some cases, spontaneous resolution of skin lesions may be
observed. An association in some parts of the world with
Borrelia burgdorferi is also noted. Patients with solitary or few
lesions can be treated with radiotherapy or surgical excision,
and chlorambucil can be used in those presenting with multi-
focal skin lesions. Intralesional or systemic anti-CD20 antibody
(rituximab) is also mentioned as a potential treatment for this
and other types of CBCL. Cytogenetic analysis has continued to
provide variable ndings with regard to t(14;18)(q32;q21),
t(11;18)(q21;q21) and t(1;14)(p22;q32) translocations.
Primary cutaneous follicular centre lymphoma
PCFCL characteristically presents with solitary or grouped
lesions, preferentially located on the scalp, forehead or trunk.
PCFCL has an excellent prognosis, with a 5-year survival of
over 95%. Multifocal skin lesions are observed in a small
minority of patients but are not associated with a more unfa-
vourable prognosis. Cutaneous relapses are observed in
approximately 10% of patients. Radiotherapy or surgery are
the preferred modes of treatment and anthracyclin-based che-
motherapy is advised in patients with extensive cutaneous dis-
ease or extracutaneous spread. The previous EORTC term of
primary cutaneous follicular centre cell lymphoma has been
replaced by the 2001 WHO term of primary cutaneous folli-
cular centre lymphoma, reecting that the tumour can have
follicular, follicular and diffuse or purely diffuse growth pat-
terns.
The constituent cells are predominantly follicular centre
small or large centrocytes and although some centroblasts can
be present, a monotonous proliferation of the latter warrants
the term primary cutaneous diffuse large B-cell lymphoma,
leg type (PCLBCL, leg type).
This does, however, place a major onus on the histopathol-
ogist to recognize these cell types accurately and to make a
distinction from, for example, reactive dendritic cells. Despite
WHOEORTC optimism that reproducible ability exists to
achieve this aim, interobserver variation in this area is gener-
ally regarded as high. The neoplastic cells consistently express
bcl-6 and recent studies suggest that PCFCL has the same
B-cell differentiation gene expression prole as germinal cen-
tre B-cell-like diffuse large B-cell lymphoma (DLBCL).
10
A
continuum of changes is observed between follicular and dif-
fuse lesions, with an increasing number of B-cell lymphocytes
but decreasing CD10, T- and CD21 dendritic cells.
11
In com-
parison with PCLBCL, leg type, the neoplastic cells are negat-
ive for multiple myeloma 1 (MUM1) interferon regulatory
factor (IRF4).
12
Unlike nodal lymphoma, histological grading
of PCFCL is not advised by the WHOEORTC as the growth
pattern and number of blast cells do not appear to have a
prognostic contribution. Published cytogenetic ndings with
regard to the presence of t(14;18) translocation and or bcl-2
expression have been variable, but in general these are often
negative. Positivity for one or both of these, however, must
raise the possibility of nodal follicular lymphoma involving
the skin. In PCFCL with a follicular growth pattern, there
appears to be no difference in clinical presentation and beha-
viour between bcl-2 and or t(14;18) positive and negative
cases. There is some evidence that expression of bcl-2 protein
by more than 50% of the neoplastic B cells in PCFCL with a
diffuse proliferation of large centrocytes may be associated
with a more unfavourable prognosis.
13
The diagnosis, clinical implications, management and treat-
ment of PCFCL are emphasized to be dramatically different
from nodal follicular lymphoma, although continuing studies
in this area are clearly indicated.
Primary cutaneous diffuse large B-cell
lymphoma, leg type
Although previously identied in the EORTC classication as
an intermediate prognosis tumour on the leg, this entity was
not recognized by the WHO in 2001. In the latter classica-
tion cases were incorporated into the general group of DLBCL.
PCLBCL, leg type characteristically involves the lower legs of
elderly women and shows a predominance of conuent sheets
of medium-sized to large cells with round nuclei and promin-
ent nucleoli resembling centroblasts and or immunoblasts.
Interestingly, the European multicentre study required at
least 50% of the cells to be large and round to enter this
2005 British Association of Dermatologists British Journal of Dermatology 2005 153, pp874880
878 The new WHOEORTC classication for cutaneous lymphomas, D.N. Slater
category.
14
Small B cells and reactive stromal T cells are relat-
ively few in number. Although the disease characteristically
presents on the leg, lesions with a similar morphology and
phenotype can arise at cutaneous sites elsewhere. This possi-
bility is accordingly acknowledged by qualifying the original
EORTC term to leg type. The theoretical possibility of, for
example, PCLBCL, leg type occurring on the cheek seems para-
doxical and raises a query as to whether the most appropriate
term has been selected. Recent studies suggest that PCLBCL,
leg type has a B-cell differentiation gene expression prole of
postgerminal centre (activated) B-cell-like DLBCL.
10
In keeping
with this, the cells consistently express MUM1 and bcl-2, and
CD10 is generally absent. Most cases are stated to express
bcl-6, although this is generally a marker of B-cell germinal
centre differentiation. Information on other immunohistologi-
cal markers of postgerminal centre plasmacellular differenti-
ation, such as CD138 (syndecan-1), are limited, but to date
the neoplastic cells have been reported as negative.
15
t(14;18)
translocation is generally absent, but recent studies have dem-
onstrated frequent translocations, similar to those in systemic
DLBCL, involving IgH, myc and bcl-6 genes.
16
Various chro-
mosomal imbalances have been described in PCLBCL, leg type
and these are present in greater number and with differences
compared with PCFCL.
17
Inactivation of p15 and p16 tumour
suppressor genes by promotor hypermethylation has been
reported in both PCFCL and PCLBCL.
18
The overall prognosis
in this group is poor, with a 5-year survival of 55% and a
tendency to disseminate to extracutaneous sites. Occurrence
on the leg and multiple lesions appear to be particular adverse
risk factors and, with the exception of single small lesions
which have a more favourable prognosis, it is recommended
that this type of lymphoma should be treated as systemic
DLBCL with anthracycline-based chemotherapy.
Primary cutaneous diffuse large B-cell
lymphoma, other
This group refers to cases of large B-cell lymphoma arising in
the skin which do not belong to the groups of PCFCL and
PCLBCL, leg type. These cases include morphological variants
of the 2001 WHO DLBCL such as anaplastic or plasmablastic
subtypes. These cases are generally a skin manifestation of
nodal lymphoma and may be seen in the setting of human
immunodeciency virus infection. In addition, rare cases of
primary cutaneous intravascular large B-cell lymphoma are
included in this category. A recent study has investigated chro-
mosomal aberrations in PCLBCL, leg type and PCLBCL, other
and has found similar aberrations irrespective of anatomical
site, cell morphology and bcl-2 expression.
19
This highlights
the similarities between these two groups of primary cutane-
ous large B-cell lymphoma designated by the WHOEORTC
and nodal DLBCL.
Some cases of primary cutaneous T-cell histiocyte-rich
B-cell lymphoma are, however, characterized by the presence
of large scattered B cells in a background of numerous
reactive T cells. Clinically, these cases appear to show greater
similarities with the groups of PCFCL and PCMZL and, unlike
their nodal counterparts, may have an excellent prognosis.
20
Conclusion
The new WHOEORTC classication for primary cutaneous
lymphomas is a much welcomed practical marriage of two
professional giants. In this, however, the EORTC has undoubt-
edly emerged as the predominant partner. Although the
EORTC has accommodated many WHO concepts, traditional
EORTC ones present themselves with substantial strength. In
addition, although previous WHO cancer classications have
been renowned for their proven evidence base, it could be
regarded as uncharacteristic for a WHO-linked classication to
admit to the requirement for new randomized multicentre tri-
als to validate some of their proposals. Somewhat perplex-
ingly, whereas EORTC concepts previously examined by the
WHO failed to gain entry into their 2001 classication, this
has now changed. Part of this new acceptance, however, has
to be acknowledged as resulting from clinical trial information
not available at the time.
The new WHOEORTC classication represents a major
improvement on the independent classications published by
the two parent organizations. There can also be no doubt that
it will end the considerable time wasted in discussing whether
countries, organizations or individuals should use the previous
EORTC or WHO classications for skin lymphoma. In addi-
tion, it will contribute signicantly to more uniform diagno-
sis, management and treatment of cutaneous lymphoma. Its
more reliable distinction between indolent and aggressive
types of cutaneous lymphoma will certainly facilitate clinical
decisions, whether to use surgical, radiotherapy, chemothera-
peutic or indeed no treatment regimens. In particular, it is
likely that the classication will actively prevent patients
receiving inappropriate high-grade treatment for low-grade
biological disease.
As acknowledged by the authors, however, this new classi-
cation is merely a new beginning and could be regarded as a
signpost indicating the direction in which research in cutane-
ous lymphoma needs to develop. New genetic ndings and
the advent of methodologies such as gene and protein expres-
sion proling will undoubtedly nd new evidence relevant to
both diagnosis and treatment and will result in the necessity
for a further updated classication in the not too distant
future. Several areas of likely future development are easily
identied. In CTCL, there will hopefully be guidance on the
early diagnosis of MF, ne tuning of the current provisional
entries under PTL, unspecied and possible subdivision of
CTCL according to Th1 and Th2 status. Russell-Jones has
recently reviewed the current and potential future status of the
diagnosis and staging of erythrodermic CTCL.
21
In CBCL,
greater emphasis will probably be given to B-cell differenti-
ation and in particular germinal centre and postgerminal
centre status. Indeed, application of this knowledge may see
the eventual disappearance of the nearly sacrosanct clinical link
between CBCL and the leg site. There is also the intriguing
2005 British Association of Dermatologists British Journal of Dermatology 2005 153, pp874880
The new WHOEORTC classication for cutaneous lymphomas, D.N. Slater 879
possibility, as with nodal follicular lymphoma, that the micro-
environment of nonmalignant tumour-inltrating immune
cells in CBCL may have prognostic relevance.
22
Furthermore,
although contrary to the ethos of current WHOEORTC thera-
peutic guidance, it perhaps should be contemplated whether
early chemotherapeutic intervention in CBCL could reduce its
signicant cutaneous relapse rate.
23
In addition, it would
appear sensible for the WHOEORTC to consider formally col-
laborating with the ISCL in its research and peer consultation
programmes.
It must also be noted that the WHOEORTC classication of
cutaneous lymphomas will be contained in the forthcoming
WHO Blue Book Series publication Tumours of the Skin (in
press). This will provide the important opportunity to include
other haematopoietic and lymphoid tumours involving the
skin as part of systemic disease.
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